Phenylacetic esters having two basic substituents and production thereof



United States Patent PHENYLACETIC ESTERS HAVING TWO BASIC SUBSTITUENTS AND PRODUCTION THEREOF Henry Najer and Pierre E. Chabrier de Lassauniere, Paris, and Pierre R. L. Giudicelli, Fontenay-sous-Bois, France, assignors to Les Laboratoires Dausse (Societe Anonyme), Paris, France, a company of France No Drawing. Filed July 25, 1958, Ser. No. 750,861

Claims priority, application France July 25, 1957 3 Claims. (Cl. 260--294.3)

In effecting synthesis of phenylacetic esters having two basic substituents, we have found that new compounds of utility for therapeutics, particularly compounds producing a spasmolytic effect and compounds producing a sedative effect on central nervous system can be provided.

Among the new compounds provided according to our invention are dibasic esters corresponding to the general Formula 1 and acid addition salts thereof from pharmaceutically acceptable acids:

In the foregoing Formula 1 R stands for a hydrogen atom,

R and R stand each for an ethyl group or, jointly with N (to which R is attached), for a piperidino group, a 1,2,5 ,6-tetrahydropyridino group or a morpholino group, or else R and R jointly represent a trimethylene chain linking the CH and N to which they are shown as attached,

R represents an ethyl group, while Ni represents a pyrrolidino, morpholino, 1,2,5,6-tetrahydropyridino, piperidino, 3-methyl-piperidino or 4- According to this invention, we further provide a process for the production of the compounds corresponding to Formula 1, wherein halo-compounds of the general formula are condensed with secondary amines of the formula H N) (the letters in the formulas having the significance mentioned with reference to Formula 1, while Hal repre- 2,952,585 Patented Sept. 13, 1950 sents a halogen atom, more particularly a chlorine atom) in the presence of an agent capable of binding the hydrogen halide H Hal, the condensation being carried out preferably in an anhydrous medium, particularly in benzene at reflux temperature.

Instead of benzene, other aromatic hydrocarbons such for example as toluene or xylene may also be employed.

All the esters corresponding to Formula 1 are spasmolytics but the B-diethylamino-ethyl a-phenyl-a-tertiaryamino-acetates are particularly desirable because they further possess a central sedative activity.

We have further found that other compounds which are also new and of interest for therapeutics, in particular as spasmolytic agents, may be obtained by condensing halo-compounds similar to those above mentioned and corresponding to the general formula with piperidine or 1,2,5,6-tetrahydropyridine, the condensation being carried out in a similar manner to that effected for producing the compounds of Formula 1.

In the general Formula 3, Hal has the same significance as above, while represents a diethylamino, morpholino or piperidino group.

The esters thus produced correspond to the general formula PyO in which 'Py represents a 1,2,5,6-tetrahydro-pyridino or a piperidino group.

The dibasic esters corresponding to the general Formulas 1 and 4 are viscous oils, which can be distilled in high vacuums and are soluble in organic solvents such as ethyl alcohol, ether and benzene but are insoluble in water. For practical use thereof it is desirable in most cases to convert said esters into water-soluble derivatives thereof, particularly acid addition salts or in the case of esters corresponding to the general Formula 4 into diquaternary ammonium compounds, in accordance with the known general methods heretofore described in the literature. In particular, dihydrochlorides and dihydrobromides may be prepared in accordance with this invention; the dihydrochlorides generally are crystalline, white compounds which are very soluble in water and insoluble in ether. Some of the diquaternary ammonium compounds from the esters of Formula 4 are curarizing agents which show a very favourable therapeutic index.

The halo compounds corresponding to the general Formulas 2 and 3 are comprised by our invention. They may be produced in accordance with known methods for the production of esters, for example from functional derivatives of a-phenyl-a-halogeno-acetic acids, particularly by reacting the chloride of such an acid with the suitable alcohol (of the formula in an anhydrous organic medium) then causing an alkali to'set the base free from the hydrochloride thereof thus produced.

The following examples will illustrate our invention.

Example 1 7 sodium chloride filtered off and washed three times-with absolute ethanol.

Ethanol was driven ofl by distilling the filtrate on a water-bath, and the residue rectified in vacuum.

Tetrahydropyridino-ethanol (42 g.; yield 66.1 percent) was collected at 80-81" C; under 6 mm. Hg. 7

' 1,2,5,6-tetrahydropyridino-ethanol was a colourless oil which was soluble in water, ethyl alcohol, ether, indeed most organic solvents. The hydrochloride thereof prepared by dissolving the base in anhydrous ether and passing dry hydrogen chloride through the ether solution, and recrystallised from a mixture of-methyl-ethylrketone and ethyl alcohol (:1) was obtained as a white, slightly hygroscopic, water-soluble, crystalline compound. The melting point thereof was 105-107 C.

Analysis-Cl (calculated) 21.71%. 21.64%.

(b) Hydrochloride of fl-diethylamino-ethyl a-phenyla-chloro-acetate: Into a solution of a-phenyl-a-chloroacetic acid chloride (245 g.; 1.29 mol) prepared according to Bischofl & Walden, Liebig-Annalen, 279, 18.94, p. 122, in anhydrous ether 1000 1111.), the solution. being cooled externally by an ice bath, a solution of e-diethylamino-ethanol (151 g.; 1.29 mol) in anhydrous ether (800 ml.) was introduced slowly (in 1 hour) while stirring continuously.

.Diethylamino-ethyl a-phenyl-a-chloro-acetate hydro- Cl (found) chloride separated immediately 'as a white, crystalline precipitate.

After the introduction was ended, the mixture was maintained for a further hour in the ice bath then left standing for 24 hours at room temperature. It was filtered, and the solid washed repeatedly with anhydrous ether then dried in air. VA crude product sample recrystallised from isobutyl alcohol had a MP. of 123 C.

tion) 4 drochloride of which 357 g. (yield 90.6%) was obtained was dissolved in water (1000 ml.). The aqueous solution was made alkaline up to pH 9 by means of a saturated aqueous solution of sodium carbonate; the diethylamino-ethyl a-phenyl-u-chloro-acetate separated as an oil which was extracted 4 times successively with ether (500 ml.).

The combined ether extracts were dried over sodium sulphate, ether driven off, and crude diethylamino-ethyl m-phenyl-a-chloro-acetate (236 g.) immediately employed in the next step to bedescribed now.

(0!) Diethylamino-ethyl a-phenyl-a-l,2,5,6-tetrahydropyridino acetate: 1,2,5,6'-tetrahydropyridine (34.8 g.; 0.42 mol) was added to a solution of diethyIamino-ethyl u-phenyl-u-chloroacetate (56.4 g.; 0.21 mol) in anhydrous benzene (250 ml.). The mixture was refluxed for 8.hours, then allowed to cool, the precipitated tetrahydropyridine hydrochloride filtered off and washed repeatedly with anhydrous benzene.

The benzene washing liquors were combined with the filtrate and benzene driven off by distillation on a Waterbath (the last traces invacuum).

The residual oil was taken up with water (200 ml.) stirred for a few minutes in a separating bulb then ex-- tracted three times with ether (200 ml. for each extrac- The combined ether extracts were dried over sodium sulphate, ether driven off and the oil distilled in a high vacuum.

We thus obtained diethylarnino-ethyl a-phenyl-u-l,2,5, 6-tetrahydropyr-idino acetate (45.5- g.; yield 68.9%) distilling at l67l70/ 0.8 mm. Hg as a viscous light yellow Y oil.

(e) Diethylamino-ethyl a-phenyl'wc-1,2,5,6-tetrahydro pyridino acetate dihydrochloride: Dry hydrogen chloride was passed through a solution of diethylamino-ethyl ecphenyl-e-l,2,5,6-tetrahydropyridino-acetate (10 g.) in anhydrous ether (400 ml.) until the precipitation was ended. The dihydrochloride was filtered off, washed twice with anhydrous ether anddniedin vacuum.

For purifying the dihydrochloride, the compound was dissolved in as little an amount of isopropanol as possible and reprecipitated therefrom by means of a big volume of anhydrous ether. 0 V V The diethylamino-ethyl u-phenyl-a-1,2,5,6tetrahydropyridino-acetate dihydro-chloride was a white compound.

which was hygroscopic to such an extent that we did not succeed in determiningthe melting point thereof.

Analysis.Cl (calculated) 18.25%. Cl (found) 17.72%.

(f) Prepared in a similar manner, the dihydrobromide had the advantage of not being hygroscopic; M.P. 200 C.; it was soluble in water and in ethyl alcohol, insoluble in methyl-ethyl-ketone.

Example 2 Working in accordance with. Example 1 but substituting fi-1,2,5,6-tetrahydropyridino-ethanol for fl-diethylaminoethanol, and pyridine for 1,2,5,6 tetrahydropyridine, we obtained successively:

(a) The 3-1,2,5,6-tetrahydropyridino-ethyl a-phenyl-achloro-acetate hydrochloride;v (yield 63.3%), being an oily substance; V

(b) The corresponding base;

(c) The 19-1,2,5,6-tetrahydropyridino ethyl e-phenyl-apiperidino'acetate (yield 61.4%), a viscous light yellow oil which distilled at l80182 C./0.05 mm. Hg;

(d) The dihydrochloride of base (0) which recrystallised from a mixture (2:1)- jof methyl-ethyl-ketone and, ethanol, was obtained. asa'white, crystalline, non-hygroscopic substance which was very soluble in water. MP. 225226 C. I

Analysis.C-l (calculated) 17.70%.p Cl (found) 7 Working in accordance with Example. 1, wefurther prepared:

5 A. The hydrochlorides of: B. The compounds tabulated below corresponding to 10 and the dihydrochlorides thereof 5 m H i R m m 5 a 1 mm DRE 0 w Fm m m Hm mmm n mm nun m u 54.8 m H m 96) mm Hw m H 1 n TL Hm Yhr. hte t w m. N w m1 m n em m N 0mm 6.6.3

a-phenyl-wchloro-acetates.

d m H n m w m m N H H N w m w m m n m m m n N n m n n w H 1 NW N H m m m 3 H H m m m m H H m m m m m m mm H n m m u w u m n N u w. u m c 1 0 w. n u n u n L, L, \h L n n m m m m m m m m w m m M m m m D O S S 0 S 0 N \J I u H 0 o u n u H o H p p n w n y m m H n n v. m v. m m u 0 W u( Lv(\ 9 9 6 8 W/\ 5 3 6 6 V. 2 2 H H H H H m 1 H H m H m am m m m m w m a m mm H a m H m m H w w H w M H w a v u u n L n n u u n u n S t 8 a u u n H m m w w m m H o o w on a 5" a w: w w w w m w u w w m m u m 2 2 M. 2 mm m m m m@ m w m m m H m m m m m r we Lo 5 H m. H or w e or 1 H e m 1 H H H m m m 1 u m H m m a Q m m m H 2 R C C C C N N N N N N N N N 2 2 2 2 a. 2 1 1 H H H H H H H H H 5 w w w m m w m w w H. H H H m H H H H H H H H H N c N 0 N 0 N lc C C C C C C G C C N N N N R NW N N N N N m N N N m m H w 0 w 0 m w c H o H o H H Base Dihydrochlorides 7 Analysis (01, R R percent) Boiling point Yield MJ? (mm. Hg) (percent) calcna found lated V 6 N- 172-174(03)--- 59.50 214 (hygrose.}.- 11.53 17.33 I ,j

N- I -GH;GH:N 189-190 (0.8). 60.70 217 17.79 17.77

Example 3 hydrochloride was obtained as a white, hygroscopic (a) Hydrochloride of diethylamino-ethoXy-ethyl uphenyl-tx-chloro-acetate: A solution of diethylaminoethoxy-ethanol (12.9 g.; 0.08 mol) in anhydrous ether (100 ml.) was added slowly (in 30 minutes) with continuous stirring to a solution of ot-phenyl-a-chloro-acetic acid chloride (15.2 g.;.0.08 mol) in anhydrous ether (100 ml.) externally cooled with an ice. bath.

The hydrochloride of diethylamino-ethoxy-ethyl aphenyl-u-c hloro-acetate separated in pasty form.

After the addition. was ended, the mixture was maintained for 2 hours in an ice bath with stirring then left standing for 24 hours at room temperature. Ether was decanted. V

(b) Diethylamino-ethoxy-ethyl a-phenyl-a-chloro acetatei The'cru'de hydrochloride (a) was dissolved inas little wateras possible. The aqueous solution was made alkaline to pH9 by means of asaturated aqueous solution of sodium carbonate; diethylamino-ethoxy-ethyl a-phenyloe-chloro-acetate separated'as an oil which was extracted 4 times successively with ether (100 ml. each time).

The combined ether extracts were dried over sodium sulphate, ether driven oil and crude dietliylamino-ethoxyethyl u-phenyl-a-chloro-acetate (22.1 g.; yield 88%) imfiltrate and benzene driven ofl by distillation on a waterbath (the last traces in vacuum).

The residual oil was taken up with water (50 ml.) stirred for a few minutes in a separating bulb then extracted 3 times with ether (1 20 ml. each time).

The combined ether extracts were dried over sodium 7 sulphate, ether driven ofi, and the oil rectified twice in a high vacuum.

Diethylamino-ethoxy-ethyl u-phenyl-a-l,2,5,6-tetrahydropyridino-acetate (10.7 g.; yield 42%) distilling at 189l91 /0.3 mm. Hg was finally obtained as a viscous, lightyellowoil.

(d) Diethylamino ethoxyethyl a-phenyl-a-1,2,5,6- tetrahydropyridino acetate dihydrochloride: A solution of hydrochloric acid inanhydrous ether was added drop by drop until precipitation was ended, to a solution of diethylaminowethoxy-ethyl. a-phenyl-a-1,2,5.,6rtetrahydropyri'dino-acetate (5.4 g.) in anhydrous ether (100 ml.). The dihydrochloride was filtered off, washed repeatedly with anhydrous ether and dried in vacuum.

Recrystallised from anhydrous acetone, the said dicrystalline compound which was soluble in water and ethylalcohol but insoluble in ethyl acetate and methylethyl-ketone; M.P. 161 C.

Analysis.-CI' (calc.) 16.39%. 01 (found) 16.04%.

(e) Diethy-lamino ethoxy ethyl u-phenyl-m-l,2,5,6- tetrahydropyridino acetate dimethiodide: Methyliodide (2.9 g.; 0.02 mol) was added to a solution of diethylamino-eth0xy-ethyl u-phenyl-a-1,2,5,6-tetrahydropyridinoacetate (3.6 g.; 0.01 mol) in anhydrous ether (15 ml.). The mixture was left standing for 3 hours at room temperature; the precipitated dirnethiodide'was filtered oil, washed with anhydrous acetone and dried in vacuum.

Diethylarnino-ethoxy-ethyl u-phenyhod,2,5,6-tetrahydropyridino-acetate dimethiodide (5.5 g.; yield 84.6 M)

after recrystallisation from absolute ethanol was finally obtained as'a white, water-soluble, non-hygroscopic, crystalline substance; M.P. 167 C.

Analysis.I (calc.) 39.44%. I (found) 39.54%.

'Working in accordance with Example 3, we further obtained: 7

(A) The hydrochloride of piperidino-ethoxy-ethyl aphenyl-a-chloro-acetate (M.P. 116 0.; yield 98%; calc. 01 9.80%; found 9.72%); Y

The hydrochloride of morpholino-ethoxy ethyl-a-phenyl-a-chloro-acetate (M.P. 84? C.; yield calc. Cl 9.75%; found 9.841%).

Piperidino ethoxy ethanol was prepared as follows:

A mixture of 2-(2'-chloro-ethoxy') -ethyl acetate (50 g. 0.3 mol) prepared according to Blicke and Biel, Journal of the American Chemical Society, 76, 1954, page 3164,

' piperidine (765 g.; 0.9 mol) and absolute alcohol (75 ml.) was heated to 120-125 C. for about 18 hours. Alcohol was driven off on a water-bath (the last traces in vacuum). The mixture was taken up with water (30 ml.) then made alkaline with 40 percent caustic soda lye (40 ml.) and. stirred for a few minutes ina separating bulb. The separated oil was then extracted 4 successive times with ether 100 ml. each time).

The combinedether extracts were dried'over sodium sulphate, ether driven off andthe residual oil rectified in vacuum.

Piperidino-ethoxy-ethanol (39.5 g.; yield 76 percent) was finally; obtained as a colourless liquid distilling at 106 C./3 mrruHg. I

The hydrochloride thereof, recrytallised from acetone, was a white, slightly hygroscopic, water-soluble, crystalline compound;,M.P. C.

Analysis.Cl (calc.) 16.94%. Cl (found) 16.94%.

Similarly prepared with a yield of 69.7 percent, morpholino ethoxy-ethanol was a colourless liquid distilling at 106-108 "C./3-mtm. Hg.

The hydrochloride thereof, recrystallised from isopropanol, was a white, water-soluble, crystalline compound; M.P. 157 C.

Analysis'..iCl (calc.) 16.78%. Cl'(found) 16.65%.

(B) The to the general formula tabulated below, corresponding the dihydrochlon'des, and the dimethiodides thereof: 7

Base Dlhydroehlorides Dlmethiodides R R 7 Analysis Analysis Boiling point Yield Melting (01, Percent) Melting (I, Percent) (mm. Hg) (Percent) point, O. pgiit,

eale. found I cale. found /C :1 Is- N N res-1'87" (0.4) v 73.8 196 39.31 as. 62 N- -N O 218-220 (1) 72 2ll-212 15.81 15.60 201 38.48 38.13

N-- N b 203-205 (0.2) 56.7 198 15.88 15.70 201 38.60 38. 39 U N N 199-200 (0.5) 76 (hygrose)- 15. 95 15.97 176 38.71 38. 87 C The various final products of the foregoing three ex- The various compounds were generally found little toxic amples (including those above tabulated) were tested 40 and effective as spasmolytics. The following three comwith a view to determining the toxicity thereof (FD pounds showed outstanding properties and are preferred:

2,952,686 11* 12 v wlmtwe claim is: e E 3. The diethylamino dimetliiodide of the formula. 1; A dimethiodide of the formula v i f lLy g N 3 wherein m U Py represents a member selected from the class consisting of 1,2,5 ,g-tetrahydropyrfdflq gro p an pipefi in References Citetf In the fiIe of this patent group, an Am represents a member selected from the cla's'sbonsi'st- 15' STATES PATENTS 7 ing of diethylamjno group, morpholino gmup and 2,830,057 Hoffman et al. Apr; 8, 1958 pipefldmo group 1 7 OTHER REFERENCES 2. The diethylamino dirfiethiqdide of the formulae Friebel a1: Naunyn Schmiedebergs Arch. ExptL 20 Pathol. Pharmakol, vol. 221, p. 261 (1954).

Mofiett et al.: I. Am. Pharm. Ass0c., vol. 42, p". 719' 

1. A DIMETHIODIDE OF THE FORMULA
 2. THE DIETHYLAMINO DIMETHIODIDE OF THE FORMULA: 